A variety of approaches have been developed to permit the delivery of an active agent, such as a drug, to a subject, preferably for the sustained release of such agent. Such delivery systems are typically designed to protect the agent from the environment prior to delivery while permitting the controlled release of the agent to the targeted area of the subject.
A number of conventional controlled release systems are based on microstructures, such as liposomes, lipospheres, microcapsules, microparticles, and nanoparticles, as well as macrostructures, such as cylinders, discs, and fibers. Typically, an active agent, such as a drug, is blended with a polymer and then formed into the desired shape.
Many of such conventional systems cannot be used to form a solid implant with the structural integrity required for prosthetic applications. Furthermore, many of such systems cannot be used to form articles that can be infused with an active agent (e.g., drug) by a physician, for example, at the time of application to the subject. Also, many of such systems include polymers that cannot be easily controlled with respect to the rate of biodegradation and/or the rate of release of any incorporated active agents.
Hydrogels (e.g., a class of polymers that are swollen in an aqueous medium but do not dissolve in water) made by the crosslinking of albumin with polyethylene glycol (PEG) derivatives have been studied previously for possible drug delivery applications (D""Urso et al., Biotech. Tech., 8, 71-76 (1994)). Another approach to the controlled delivery of drugs involves microencapsulation or microsphere formation with the use of synthetic bioabsorbable polymers such as poly(lactic acid) and various copolymers of lactide and glycolide. A drawback to the use of microspheres, however, is that they cannot be coated evenly and retained on the surface of a surgical site or on injured or diseased tissue. To address this problem, microsphere-containing membranes have been made by suspending the microspheres in a solution of a second polymer made with the use of a solvent that is a nonsolvent for the microspheres and then casting a film out of the mixture.
Thus, there is a need for other delivery systems, particularly for one that includes a polymer composition that can be varied to provide a range of biodegradation rates and delivery rates. Preferably, there is a need for a delivery system that includes a polymer composition that has sufficient structural integrity to be easy to handle.
The present invention provides a preformed object for delivering an active agent to a subject, the preformed object being at least partially desolvated crosslinked albumin having a crosslinking agent of the formula:
Ixe2x80x94(xe2x80x94Xxe2x80x94LMxe2x80x94G)n
wherein:
X is a difunctional polyoxyethylene chain portion or a bond;
LM is a difunctional linking moiety represented by the formulas xe2x80x94C(O)xe2x80x94, xe2x80x94(CH2)bC(O)xe2x80x94 where b is an integer from 1 to 5, xe2x80x94C(O)xe2x80x94(CH2)cxe2x80x94C(O)xe2x80x94 where c is an integer from 2 to 10 and where the aliphatic portion of the radical may be saturated or unsaturated, xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)dxe2x80x94Oxe2x80x94C(O)xe2x80x94 where d is an integer from 2 to 10, or an oligomeric diradical represented by the formulas xe2x80x94Rxe2x80x94C(O)xe2x80x94, xe2x80x94Rxe2x80x94C(O)xe2x80x94(CH2)cxe2x80x94C(O)xe2x80x94, or xe2x80x94Rxe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)dxe2x80x94Oxe2x80x94C(O)xe2x80x94 where c is an integer from 2 to 10, d is an integer from 2 to 10, and R is a polymer or copolymer having 1 to 10 monomeric lactide, glycolide, trimethylene carbonate, caprolactone or p-dioxanone fragments;
G is a leaving group selected from the group of N-oxysuccinimidyl, N-oxymaleimidyl, N-oxyphthalimidyl, nitrophenoxyl, N-oxyimidazolyl, and tresyl;
I is a multifunctional linking moiety derived from a multinucleophilic compound; and
n is an integer from 2 to 10;
with the proviso that when X is a difunctional polyoxyethylene chain portion xe2x80x94Xxe2x80x94Ixe2x80x94Xxe2x80x94 is PEG, which is a diradical fragment represented by the formula:
xe2x80x83xe2x80x94Oxe2x80x94(CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)axe2x80x94
wherein a is an integer from 20 to 300.
Other embodiments of the present invention include such preformed objects with an active agent incorporated therein, which may or may not be resolvated, and such preformed objects having an active agent therein further incorporated into a secondary biodegradable matrix. Other embodiments include preformed objects of other biodegradable polymers having an active agent therein further incorporated into a secondary biodegradable matrix, which is of the chemistry described above for the preformed objects. Methods of making and methods of delivering an active agent to a subject are also provided by the present invention.